Tuberous sclerosis is an autosomal dominant disorder that causes morbidity and mortality due to seizures, mental retardation, hamartomas, and benign and malignant neoplasms. While two genes for TS have been cloned, hamartin (tsc1) and tuberin (tsc2), the mechanism behind the tissue specificity of hamartomas and neoplasms are poorly understood. In addition, no phenotype-genotype correlation has been established in TS. These tissues are not specific to TS, but exist in other autosomal dominant syndromes like neurofibromatosis, not only in which neoplasms occur, but also hamartomas which cause learning disabilities and hypertension. The bewildering array of disorders which occur in TS patients suggest that modifying genes regulate the TS phenotype. We will analyze the effect of a candidate modifying gene, HDAC9, on the phenotype of transgenic mice we have already generated which carry a specific modification in the tuberin gene and which develop hamartomas.